Constitutive Activation of the Angiotensin II Type 1 Receptor Alters the Spatial Proximity of Transmembrane 7 to the Ligand-binding Pocket

Activation of G protein-coupled receptors by agonists involves significant movement of transmembrane domains (TM) following binding of agonist. The underlying structural mechanism by which receptor activation takes place is largely unknown but can be inferred by detecting variability within the environment of the ligand-binding pocket, which constitutes a water-accessible crevice surrounded by the seven TM helices. Using the substituted cysteine accessibility method, we initially identified those residues within the seventh transmembrane domain (TM7) of wild type angiotensin II type 1 (AT1) receptor that contribute to forming the binding site pocket. We have substituted successively TM7 residues ranging from Ile276 to Tyr302 to cysteine. Treatment of A277C, V280C, T282C, A283C, I286C, A291C, and F301C mutant receptors the which that residues within the water-accessible binding of the of TM7 a mutant of the that TM7 of the receptor a of that from the binding of TM7 of activation of the receptor structural Activation of G protein-coupled receptors by agonists involves significant movement of transmembrane domains (TM) following binding of agonist. The underlying structural mechanism by which receptor activation takes place is largely unknown but can be inferred by detecting variability within the environment of the ligand-binding pocket, which constitutes a water-accessible crevice surrounded by the seven TM helices. Using the substituted cysteine accessibility method, we initially identified those residues within the seventh transmembrane domain (TM7) of wild type angiotensin II type 1 (AT1) receptor that contribute to forming the binding site pocket. We have substituted successively TM7 residues ranging from Ile276 to Tyr302 to cysteine. 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